Protective effect of baicalin on experimental pulmonary arterial hypertension through inhibition of pulmonary vascular remodeling

doi:10.5246/jcps.2020.10.067

Abstract

Abstract:

Previous studies have shown that baicalin can attenuate pulmonary arterial hypertension and right ventricular hypertrophy. However, the potential mechanism remains unexplored. Nuclear factor-κB (NF-κB) and bone morphogenetic protein (BMP) signaling pathway play an important role in monocrotaline (MCT) induced pulmonary arterial hypertension (PAH). Therefore, we aimed to observe the regulation of baicalin on the NF-κB-BMP axis and the subsequent anti-proliferation in pulmonary vascular. Our results showed that baicalin could significantly decrease right ventricular systolic pressure (RVSP) and the RV/left ventricle plus septum ratio (P < 0.05), and attenuate vascular remodeling. Furthermore, the result of westen blot showed that the protein expression level of BMP receptor 2 (BMPR2) was significantly increased, while NF-κB p65, p-NF-κB p65, inhibitor of NF-κB (I-κBα) and the BMP antagonist, gremlin 1 were significantly down-regulated in the baicalin group (P < 0.05). On the other hand, the result of immunohistochemical staining in lung showed that the capillary density of pulmonary arterioles significantly increased in the baicalin group compared with the MCT group (P < 0.05). We concluded that baicalin exerted the protective effects against the lung and heart damage through inhibiting NF-κB-BMP signaling pathway, providing new mechanistic information about PAH and right ventricular hypertrophy.

Key words: Baicalin, Pulmonary arterial hypertension, Pulmonary vascular remodeling, NF-κB, BMP

CLC Number:

R961.1

Supporting:

Wen Jiang, Chao Sun, Jue Wang, Qian Xin, Kailin Li, Tonggang Qi, Yun Luan. Protective effect of baicalin on experimental pulmonary arterial hypertension through inhibition of pulmonary vascular remodeling[J]. Journal of Chinese Pharmaceutical Sciences, 2020, 29(10): 719-728.

References

[1] Yang, J.; Li, X.H.; Al-Lamki, R.S.; Southwood, M.; Zhao, J.; Lever, A.M.; Grimminger, F.; Schermuly, R.T.; Morrell, N.W. Smad-dependent and smad-independent induction of Id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo. Circ. Res. 2010, 107, 252-262.

[2] Lavoie, J.R.; Ormiston, M.L.; Perez-Iratxeta, C.; Courtman, D.W.; Jiang, B.H.; Ferrer, E.; Caruso, P.; Southwood, M.; Foster, W.S.; Morrell, N.W.; Stewart, D.J. Proteomic analysis implicates translationally controlled tumor protein as a novel mediator of occlusive vascular remodeling in pulmonary arterial hypertension. Circulation. 2014, 129, 2125-2135.

[3] Pietra, G.G.; Capron, F.; Stewart, S.; Leone, O.; Humbert, M.; Robbins, I.M.; Reid, L.M.; Tuder, R.M. Pathologic assessment of vasculopathies in pulmonary hypertension. J. Am. Coll. Cardiol. 2004, 43, S25-S32.

[4] Pietra, G.G.; Edwards, W.D.; Kay, J.M.; Rich, S.; Kernis, J.; Schloo, B.; Ayres, S.M.; Bergofsky, E.H.; Brundage, B.H.; Detre, K.M. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation. 1989, 80, 1198-1206.

[5] Zhao, C.F.; Wang, L.J.; Gao, L.; Xia, W.; Wang, Z.Y.; Li, F.H. Changes and distributions of peptides derived from proadrenomedullin in left-to-right shunt pulmonary hypertension of rats. Circ. J. 2008, 72, 476-481.

[6] Stenmark, K.R.; Fagan, K.A.; Frid, M.G. Hypoxia-induced pulmonary vascular remodeling cellular and molecular mechanisms. Circ. Res. 2006, 99, 675-691.

[7] Hosokawa, S.; Haraguchi, G.; Sasaki, A.; Arai, H.; Muto, S.; Itai, A.; Doi, S.; Mizutani, S.; Isobe, M. Pathophysiological roles of nuclear factor kappa B (NF-kB) in pulmonary arterial hypertension: effects of synthetic selective NF-kB inhibitor IMD-0354. Cardiovasc. Res. 2013, 99, 35-43.

[8] Wang, Y.Y.; Luan, Y.; Zhang, X.; Lin, M.; Zhang, Z.H.; Zhu, X.B.; Ma, Y.; Wang, Y.B. Proteasome inhibitor PS-341 attenuates flow-induced pulmonary arterial hypertension. Clin. Exp. Med. 2014, 14, 321-329.

[9] Jin, U.H.; Suh, S.J.; Chang, H.W.; Son, J.K.; Lee, S.H.; Son, K.H.; Chang, Y.C.; Kim, C.H. Tanshinone IIA from Salvia miltiorrhiza BUNGE inhibits human aortic smooth muscle cell migration and MMP-9 activity through AKT signaling pathway. J. Cell. Biochem. 2008, 104, 15-26.

[10] Kumar, S.; Wei, C.; Thomas, C.M.; Kim, I.K.; Seqqat, R.; Kumar, R.; Baker, K.M.; Jones, W.K.; Gupta, S. Cardiac-specific genetic inhibition of nuclear factor-κB prevents right ventricular hypertrophy induced by monocrotaline. Am. J. Physiol. Heart Circ. Physiol. 2012, 302, H1655-H1666.

[11] Luan, Y.; Chao, S.; Ju, Z.Y.; Wang, J.; Xue, X.; Qi, T.G.; Cheng, G.H.; Kong, F. Therapeutic effects of baicalin on monocrotaline-induced pulmonary arterial hypertension by inhibiting inflammatory response. Int. Immunopharmacol. 2015, 26, 188-193.

[12] Shen, Y.C.; Chiou, W.F.; Chou, Y.C.; Chen, C.F. Mechanisms in mediating the anti-inflammatory effects of baicalin and baicalein in human leukocytes. Eur. J. Pharmacol. 2003, 465, 171-181.

[13] Chen, Y.; Hui, H.; Yang, H.; Zhao, K.; Qin, Y.S.; Gu, C.; Wang, X.T.; Lu, N.; Guo, Q.L. Wogonoside induces cell cycle arrest and differentiation by affecting expression and subcellular localization of PLSCR1 in AML cells. Blood. 2013, 121, 3682-3691.

[14] Woo, A.Y.H.; Cheng, C.H.K.; Waye, M.M.Y. Baicalein protects rat cardiomyocytes from hypoxia/reoxygenation damage via a prooxidant mechanism. Cardiovasc. Res. 2005, 65, 244-253.

[15] Lin, L.; Wu, X.D.; Davey, A.K.; Wang, J.P. The anti-inflammatory effect of baicalin on hypoxia/reoxygenation and TNF-α induced injury in cultural rat cardiomyocytes. Phytother. Res. 2010, 24, 429-437.

[16] Zhang, L.; Pu, Z.C.; Wang, J.S.; Zhang, Z.F.; Hu, D.M.; Wang, J.J. Baicalin inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via the AKT/HIF-1α/p27-associated pathway. Int. J. Mol. Sci. 2014, 15, 8153-8168.

[17] Dong, L.H.; Wen, J.K.; Miao, S.B.; Jia, Z.H.; Hu, H.J.; Sun, R.H.; Wu, Y.L.; Han, M. Erratum: Baicalin inhibits PDGF-BB-stimulated vascular smooth muscle cell proliferation through suppressing PDGFRβ-ERK signaling and increase in p27 accumulation and prevents injury-induced neointimal hyperplasia. Cell Res. 2011, 21, 1276.

[18] Ikezoe, T.; Chen, S.S.; Heber, D.; Taguchi, H.; Koeffler, H.P. Baicalin is a major component of PC-SPES which inhibits the proliferation of human cancer cells via apoptosis and cell cycle arrest. Prostate. 2001, 49, 285-292.

[19] D’Alto, M.; Mahadevan, V.S. Pulmonary arterial hypertension associated with congenital heart disease. Eur. Respir. Rev. 2012, 21, 328-337.

[20] Dai, H.L.; Guo, Y.; Guang, X.F.; Xiao, Z.C.; Zhang, M.; Yin, X.L. The changes of serum angiotensin-converting enzyme 2 in patients with pulmonary arterial hypertension due to congenital heart disease. Cardiology. 2013, 124, 208-212.

[21] Li, L.; Wei, C.; Kim, I.K.; Janssen-Heininger, Y.; Gupta, S. Inhibition of nuclear factor-κB in the lungs prevents monocrotaline-induced pulmonary hypertension in mice. Hypertens. Dallas Tex. 2014, 63, 1260-1269.

[22] Zhang, X.; Wang, Z.S.; Luan, Y.; Lin, M.; Zhu, X.B.; Ma, Y.; Zhang, Z.H.; Wang, Y.B. The effect of PS-341 on pulmonary vascular remodeling in high blood flow-induced pulmonary hypertension. Int. J. Mol. Med. 2014, 33, 105-110.

[23] Chen, Y.; Hui, H.; Yang, H.; Zhao, K.; Qin, Y.S.; Gu, C.; Wang, X.T.; Lu, N.; Guo, Q.L. Wogonoside induces cell cycle arrest and differentiation by affecting expression and subcellular localization of PLSCR1 in AML cells. Blood. 2013, 121, 3682-3691.

[24] Morrell, N.W.; Bloch, D.B.; Dijke, P.T.; Goumans, M.J.T.H.; Hata, A.; Smith, J.; Yu, P.B.; Bloch, K.D. Targeting BMP signalling in cardiovascular disease and anaemia. Nat. Rev. Cardiol. 2016, 13, 106.

[25] Lowery, J.W.; Frump, A.L.; Anderson, L.; DiCarlo, G.E.; Jones, M.T.; de Caestecker, M.P. ID family protein expression and regulation in hypoxic pulmonary hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010, 299, R1463-R1477.

[26] Ciumas, M.; Eyries, M.; Poirier, O.; Maugenre, S.; Dierick, F.; Gambaryan, N.; Montagne, K.; Nadaud, S.; Soubrier, F. Bone morphogenetic proteins protect pulmonary microvascular endothelial cells from apoptosis by upregulating α-B-crystallin. Arterioscler. Thromb. Vasc. Biol. 2013, 33, 2577-2584.

[27] Kumar, S.; Wei, C.; Thomas, C.M.; Kim, I.K.; Seqqat, R.; Kumar, R.; Baker, K.M.; Jones, W.K.; Gupta, S. Cardiac-specific genetic inhibition of nuclear factor-κB prevents right ventricular hypertrophy induced by monocrotaline. Am. J. Physiol. Heart Circ. Physiol. 2012, 302, H1655-H1666.

[28] Hurst, L.A.; Dunmore, B.J.; Long, L.; Crosby, A.; Al-Lamki, R.; Deighton, J.; Southwood, M.; Yang, X.D.; Nikolic, M.Z.; Herrera, B.; Inman, G.J.; Bradley, J.R.; Rana, A.A.; Upton, P.D.; Morrell, N.W. TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Nat. Commun. 2017, 8, 14079.

[29] Murphy, N.; Gaynor,K.U.; Rowan,S.C.; Walsh, S.M.; Fabre, A.; Boylan, J.; Keane, M.P.; McLoughlin, P. Altered expression ofbone morphogenetic protein accessory proteins in murine and human pulmonary fibrosis. Am. J. Pathol. 2016, 186, 600-615.

[30] Arciniegas, E.; Frid, M.G.; Douglas, I.S.; Stenmark, K.R. Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension. Am. J. Physiol. Lung Cell Mol. Physiol. 2007, 293, L1-L8.

[31] Willis, B.C.; Borok, Z. TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am. J. Physiol. Lung Cell Mol. Physiol. 2007, 293, L525-L534.

[32] Alastalo, T.P.; Li, M.L.; Perez, V.D.J.; Pham, D.; Sawada, H.; Wang, J.K.; Koskenvuo, M.; Wang, L.L.; Freeman, B.A.; Chang, H.Y.; Rabinovitch, M. Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J. Clin. Investig. 2011, 121, 3735-3746.